Hypercalciuria and Bone Quality in the Genetic Hypercalciuric Stone-Forming Rat. The primary end point for successful treatment of patients with calcium (Ca) containing kidney stones is a decrease in the rate of stone recurrence. While this is an important goal, equally important is maintaining and improving the patient's bone mineral density (BMD) and bone quality. The majority of human kidney stone formers with Ca-containing kidney stones is hypercalciuric and often excretes more Ca than they absorb indicating a net loss of total body Ca. The source of this additional urine (U) Ca is almost certainly the skeleton. BMD is correlated inversely with UCa excretion. Many studies demonstrate that nephrolithiasis patients have a reduction in BMD and have an increased risk of fractures. To help understand the mechanism of idiopathic hypercalciuria in man, we developed an animal model of this disorder. Through >90 generations of successive inbreeding we established a strain of rats that now consistently excrete ~8-10 times as much urinary Ca as controls. As all of these rats form kidney stones, they have been termed genetic hypercalciuric stone-forming (GHS) rats. The GHS rats have a systemic abnormality in Ca homeostasis: they absorb more intestinal Ca, resorb more bone, and do not adequately reabsorb filtered Ca. The bone, kidney and intestine in the GHS rats have an increased number of vitamin D receptors (VDR) which may be regulated by a decreased level of the transcription factor Snail, suggesting potential underlying mechanism(s) for the hypercalciuria. We have recently found that the GHS rats have reduced cortical and trabecular BMD and decreased trabecular volume and thickness on an ample Ca diet. Their bones are brittle and fracture prone. The thiazide diuretic chlorthalidone increased their trabecular bone strength. The overall goal of this proposal is to study the relationship of hypercalciuria to BMD and bone quality in GHS rats. Since they have decreased BMD and bone quality, we propose to study their basic bone biology. We propose to explore the Snail, VDR, hypercalciuria, bone axis. We will then ask if dietary modifications to reduce hypercalciuria and stone formation will improve BMD and bone quality. We propose the following Specific Aims: 1. Test the hypothesis that the decreased BMD and bone quality in the GHS rats, compared to the parental Sprague-Dawley rats, is due primarily to enhanced bone resorption, and not decreased bone formation. 2. Test the hypothesis that suppression of Snail in GHS rats is due to either decreased signal(s) that up-regulate Snail (TGF2-1, BMP2) or enhanced signals that down-regulate Snail (miRs let-7 family). 3. Test the hypothesis that the reduced BMD and bone quality in the GHS rats can be improved by dietary measures directed toward reducing hypercalciuria. With these studies we hope to better understand the pathogenesis of hypercalciuria and decreased BMD. If the results from these studies are supported by studies in human hypercalciuric stone formers, they will have a substantial effect on treatment paradigms that will not only reduce recurrent stone formation but improve BMD and bone quality in hypercalciuric patients.